Generalized anxiety disorder (GAD) is an underserved therapeutic area where viable drug targets in psychopharmacology in general are in a severe state of drought. Few viable alternatives other than benzodiazepines (BZs), like diazepam, are used for the treatment of GAD. The clinical usefulness of the BZs for GAD is severely limited by side effects such as sedation, memory loss, etc. Therefore, drug discovery efforts to improve BZs have focused on compounds selective for GABAA ? subunits because activation of specific ? subunits may account for anxioselective effects. For example, BZs selective for the ?2/??3 subunit may be anxiolytic without sedation. This concept is yet to be clinically validated. Compounds that bind to novel allosteric sites on the GABAA receptor might modulate the action of GABA in a manner superior to BZs. A particular group of non-BZ compounds that elicit greater GABA activity in ?2/??3 GABAA subunit containing receptors relative to receptors containing ?1 subunits are known in the literature like tracazolate, loreclezole, etifoxine and mefenamic acid. Several of these compounds have gone through clinical trials and/or are clinically available. Moreover these compounds have a reduced sedative potential relative to BZs. Are compounds with minimal or no activity at ?1 subunit containing receptors like these early generation compounds less likely to cause sedative effects? We have developed compounds in this laboratory that are several orders of magnitude more potent than this older generation of ?2/??3 selective modulators. These ? selective enaminones show minimal to no activity at ?1 subunit containing receptors. We will characterize enaminones and their SARs for ? subunit selectivity as a timely first-step in the identification of a new generation of anxiolytics that do not act at the BZ receptor yet retain the full anxiolytic efficacy of the BZs but with fewer side effects. The proposed studies will identify high potency enaminones with varying efficacies to activate ?1 subunit containing receptors. Candidate compounds will be tested in simple animal models of sedation and anxiety after pharmacokinetics of CNS penetration are determined. Completion of the proposed studies will yield a suitable candidate(s) that will be the topic of future studies to fully characterize in vivo pharmacology and site of action, with the ultimate goal of developing a novel drug(s) for the treatment of anxiety disorders. The Public Health Relevance: The US public health costs of anxiety disorders are estimated to be $42B a year. Anxiety disorders are highly treatable, yet only about one-third of those suffering from an anxiety disorder receive treatment. The focus of the proposed project is to develop therapeutics to bolster the shortfall of therapies for the treatment of anxiety disorders, an underserved therapeutic area that affects 3.1% of the general population over 18.